Compounds useful for perhalogenoalkylation, reagent for implementing these compounds and synthesis method for obtaining these compounds

ABSTRACT

The invention concerns a reagent and a family of compounds. The reagent contains by successive or simultaneous addition: a material of formula RfH, a silicophilic base, a trivalent nitrogenous derivative containing no hydrogen and at least two silyl groups. The invention is useful for organic synthesis.

This application is an application under 35 U.S.C. Section 371 ofInternational Application Number PCT/FR97/02062, filed on Nov. 17, 1997.

The present invention relates to a process useful forperfluoroalkylation and to a reagent for implementing this process. Itrelates more particularly to a reagent and a process for grafting asubstituted difluoromethyl group onto a compound containing at least oneelectrophilic functional group. It relates more particularly to atechnique for perfluoroalkylating various compounds by nucleophilicsubstitution or addition reactions which are typically carried out byorganometallic derivatives.

Perfluoroalkylation or equivalent techniques generally employderivatives of the perfluoroalkyl bromide or iodide type in the presenceof zinc. This technique is therefore expensive, and necessitatesinstallations for processing the metallic wastes, which need to betreated since zinc is a major pollutant of waterways. Furthermore,compounds of the trifluoromethyl bromide type contribute considerably tothe greenhouse effect.

Other techniques, in which the perfluoroalkyl radical does not form astabilized reactive intermediate of the organometallic type, aregenerally difficult to implement owing to the very low stability of thefree perfluorinated anions in the reaction media. These techniquesgenerally lead to products of the carbene type which, when they react,have lost one of their substituents. Therefore, one of the aims of thepresent invention is to provide a reagent which permitsperfluoroalkylation according to a mechanism of the type involving acarbanion without requiring the use of organometallic compounds oftransition metals such as zinc.

Attempts have often been made to use perfluorocarboxylic acids as asource of perfluoroalkyl radicals and, more generally, oftrifluoromethyl radicals, by employing decomposition reactions whose aimis to remove the carboxyl fragment of the said acids, in the course ofwhich carbon dioxide is released. However, the successes which have beenachieved have been very modest and have used particularly complexcatalyst systems. The perfluoroalkyl radicals, or their equivalents,brought into being by the decomposition of the said perfluorocarboxylicacids, moreover, have been unstable in the reaction medium and havenecessitated the use of stabilizers.

More recently, Shono, in an article entitled “a noveltrifluoromethylation of aldehydes and ketones promoted by anelectrogenerated base” and published in J. Org. Chem. 1991, 56, 2-4,attempted to carry out perfluoromethylation reactions starting fromfluoroform and showed that it was very difficult to obtain positiveresults in the absence of the base consisting of the pyrrolidonyl anionin combination with a quaternary ammonium cation and that this was soonly subject to the express proviso that the said base had been broughtinto being by electrolysis.

In the course of this comparative study, which took as the test reactionthe trifluoromethylation of benzaldehyde by the technique known asBarbier's technique (which consists in adding base and fluoroform to thesubstrate), this author concluded that the results obtained startingfrom other bases gave yields which were zero or mediocre and that thecompeting reactions, and especially the Cannizaro reaction (dismutationof benzaldehyde to benzoic acid and benzyl alcohol), were predominant[however, the procedures relating to the usual bases (potassiumtert-butoxide, sodium hydride, etc) are not described therein].

However, the techniques described by this author and using bases broughtinto being by electrolysis require, on the one hand, a complex apparatusand, on the other hand, such dexterity that they are difficult toreproduce and extremely difficult to scale up to the industrial scale.Finally, the use of quaternary ammoniums, which are very hygroscopic,involves a great deal of care.

The object of the present invention is to overcome the disadvantages ofthe existing processes by providing an environmentally benign reagentwhich is capable of leading to the desired products with a satisfactoryyield.

Another aim of the present invention is to provide reagents andoperating conditions which overcome the disadvantages of quaternaryammoniums and which therefore allow them to be used.

These aims and others which will become evident below are achieved bymeans of a reagent which comprises at least one of the compounds offormula:

in which Y represents a chalcogen atom, advantageously oxygen;

M⁺ represents a cation, advantageously a monovalent cation andpreferably a cation selected from alkali metals and phosphoniums;

R₁ is a radical selected from hydrogen, hydrocarbon radicals such asaryl (including alkylaryl) and alkyl (including aralkyl and cycloalkyl);

R₂ is a radical selected from hydrocarbon radicals such as aryl(including alkylaryl), alkyl (including aralkyl and cycloalkyl), andfrom amine functions, which are advantageously persubstituted (that is,their nitrogen no longer carries hydrogen), acyloxy functions andhydrocarbyloxy functions, with the provisos that, when M⁺ is alkalimetal or phosphonium and R1 is hydrogen, R2 is neither phenyl nordimethylamino;

and that, when M+ is quaternary ammonium, the said reagent additionallycomprises at least [lacuna] trivalent nitrogen derivative which ispersilylated (by persilylated is meant a derivative which contains nohydrogen and at least two silyl groups, preferably three);

and which reagent can be obtained by contacting, in a polar medium whichis non-protic or not very protic, a substance of formula RfH and a basewith a substrate which carries at least one double bond of the type >C═Yand has the formula

The addition compound of fluoroform with DMF had possibly already beenobtained, although not identified, during the test (by the Grignardmethod) used as an example in the French application FR95/13996, whichwas unpublished on the filing date of the earliest priority application(FR96/14133) of the present application.

According to the present invention, the said reagent can additionallycomprise a polar solvent (or solvent mixture) which is non-protic or notvery protic.

According to a preferred embodiment, the said compound of formula IV ispresent in a concentration of at least one millimole per liter,advantageously at least 5 millimoles per liter and, preferably, 10millimoles per liter.

The abovementioned reagent can be obtained by the use of anotherreagent, which is also useful for obtaining a fluoro derivative andwhich comprises, for successive or simultaneous addition:

a silicophilic base; and

a substance of formula Rf—Z where Z is selected from hydrogen and—Si(R′)₃, in which the radicals R′ are identical or different and arehydrocarbon radicals of 1 to about 20 carbon atoms, advantageously 1 to10 and, preferably, 1 to 5, the total carbon number of Rf—Si(R′)₃ beingadvantageously not more than 50, preferably not more than 30;

with the proviso that, if Z is hydrogen, it additionally comprises apersilylated trivalent nitrogen derivative, advantageously in an atleast stoichiometric amount.

The persilylated trivalent nitrogen derivative can in particular be apersilylated amide whose anion is highly basic (for example persilylatedformamide); however, preference is given to persilylated amines.

For various reasons, especially that of economy, the case where Z is His preferred. In this case, the reagent comprises, for successive orsimultaneous addition:

a substance of formula RfH;

a silicophilic base; and

a persilylated trivalent nitrogen derivative.

The reaction can be represented as follows:

RfH+B⁻+>N—Si(R′)₃→Rf⁻+>NH+B—Si(R′)₃

with, in general, an equilibrium as follows:

Rf⁻+>NH←→RfH+>N⁻

It is desirable for the base obtained (>N⁻) after desilylation of thesaid persilylated trivalent nitrogen derivative to be at least as strongas the methoxide and, advantageously, as the ethoxide of sodium.

According to the present invention, the said reagent may additionallycomprise a polar solvent (or solvent mixture) which is non-protic or notvery protic.

The cation (or cations) associated with the said silicophilic base is(are) advantageously selected from quaternary ammoniums, quaternaryphosphoniums and alkali metals.

If it is desired to avoid the use of quaternary ammoniums, the cation(or cations) associated with the said silicophilic base is (are)preferably selected from quaternary phosphoniums and alkali metals(advantageously those whose rank is at least equal to that of sodium).

However, according to the present invention, the technique facilitatesthe use of quaternary ammonium and so the cation (or cations) associatedwith the said silicophilic base can be selected from quaternaryammoniums.

When they are alkali metals, the cation (or cations) associated with thesaid silicophilic base is (or are) selected from alkali metals whoseatomic number is at least equal to, preferably greater than, that ofsodium.

For its part, the silicophilic anion of the bases is advantageouslyselected from those capable of forming a bond with a silyl having anenergy of at least 110 kcal per mole, advantageously of approximately120 and, preferably, 130 (cf. R. Walsh, Acc. Chem. Res.; when thesilicophilic base is used with a tetrahedral silylated derivative, it ispreferable to select, as the base, fluorine or an alkoxide whose PK_(a)is higher than that of the tetrahedral compound).

According to one advantageous embodiment of the present invention, theanion of the bases is selected from fluoride and its complexes alkoxideanions and mixtures thereof. As far as the alkoxides are concerned itmay be noted that, especially in the presence of a persilylatedtrivalent nitrogen derivative, they have a pK_(a) of at least 6,advantageously 8 and, preferably, 9.

The said silicophilic base is selected in particular from fluorides andalkoxides, including the alkoxides of formula Rf(R₅)(R₆)C—O⁻ in which Rfis as defined above and R₅ and R₆ are selected from hydrogen andhydrocarbon radicals and advantageously do not represent a strongelectron-attracting group; in other words, it is preferred to selectfunctional groups whose Hammett constant σ_(p) is not more than 0.2,more preferably not more than 0.1.

The tetrahedral anion obtained with the compounds of carbonyl type istherefore generally silicophilic per se. In this case, therefore, thebase can be used in a catalytic amount (advantageously from {fraction(1/50)} to ½, preferably from {fraction (1/20)} to ⅓, of the SA (thatis, the stoichiometric amount)). It should be emphasized that thistechnique overcomes some disadvantages of the use of quaternaryammoniums and makes it possible to avoid the need to use bases broughtinto being by electrolysis. It leads directly to compounds which are atleast partly silylated.

Therefore, this process consists in reacting a compound of formula>N—Si(R′)₃ with a base which (or whose anion) is silicophilic, where theradicals R′, which are identical or different, are hydrocarbon radicalsof 1 to approximately 20 carbon atoms, advantageously 1 to 10 and,preferably, 1 to 5, the total carbon number of >N—Si(R′)₃ beingadvantageously not more than 50, preferably not more than 30. The silylradicals referred to in the present description advantageously have thesame characteristics.

Advantageously, the said silicophilic anion is selected from fluoride,its complexes (for example TBAT), oxygen-containing anions[advantageously alkoxide and especially perfluorocarbinolate (perfluoroin the sense of Rf)] and mixtures thereof.

The said persilylated trivalent nitrogen derivative advantageously has amolecular mass of not more than about 1000. It therefore possesses notmore than about 50 carbon atoms, and is preferably selected frompersilylated ammonia and persilylated primary amines and mixturesthereof. The various silyl groups can be different or the same, althoughit is simpler and more economic if they are the same.

According to one particularly advantageous embodiment of the presentinvention, the anion of the bases and the said persilylated trivalentnitrogen derivative are selected such that the silylated anion has aboiling point under atmospheric pressure of not more than about 100° C.,advantageously not more than 50° C. This property makes it possible toshift the equilibrium more easily by the progressive removal ofB—Si(R′)₃ [and even makes it possible to remove it at the rate at whichit is formed, optionally under reduced pressure], thereby permitting theuse of a relatively weak base.

In order to do this, it is advisable to ensure that the said reagentcomprises a gaseous phase in which the partial pressure of the silylatedanion is lower, at the saturation pressure under the operatingconditions, than that of the said silylated anion.

The said reagent advantageously comprises, in addition, at least onecompound (which may also be the solvent) which carries at least onedouble bond of the type >C═Y in which Y represents a nitrogen, which isadvantageously substituted, or, more preferably, a chalcogen atom. Thesecompounds either are a vector of the unit designated by Rf⁻ or form withRf⁻ a reaction intermediate.

In this case, the reagent thus obtained by contacting in a polar andnon-protic or not very protic medium a substance of formula RfH and abase with a substrate which carries at least one double bond of thetype >C═Y in which Y represents a nitrogen, which is advantageouslysubstituted, or, more preferably, a chalcogen atom (advantageouslysulphur or, more generally, oxygen) is fairly stable and makes itpossible to constitute either a high-quality reaction intermediate or aperfluoroalkylating reagent.

The conditions for the use of the above reagents are substantially thesame and are set out below.

In the present description, H—Rf means radicals of the formula:

H—(CX₂)_(p)—GEA  (II)

in which the radicals X, which are identical or different, representfluorine or a radical of formula C_(n)F_(2n+1) where n is an integer notmore than 5, preferably not more than 2, or else represent chlorine;

p represents an integer which is at least 1 and not more than 2;

GEA represents an electron-attracting group whose functions, whereappropriate, are inert under the reaction conditions, advantageouslyfluorine or a perfluorinated radical of formula C_(n)F_(2n+1) where n isan integer not more 8, advantageously not more than 5.

Advantageously, X can be chlorine only once on the same carbon. The casein which the carbon bearing the hydrogen atom has two radicals X otherthan chlorine is particularly advantageous.

It is also desirable that, among the radicals X and GEA, at least one,advantageously 2, are (chlorine or fluorine) atoms.

The total carbon number of Rf is advantageously between 1 and 15,preferably between 1 and 10.

In the substance RfH of the reagent of the invention, the unit GEA,which exerts an electron-attracting effect on the difluorinated carbonatom, is preferably selected from functional groups whose Hammettconstant σ_(p) is at least 0.1. It is also preferable for the inductivecomponent of σ_(p), σ_(i), to be at least 0.2, advantageously at least0.3. In this context reference may be made to the work by March,“Advanced Organic Chemistry”, third edition, John Wiley and Sons, pages242 to 250, and in particular to Table 4 of that section.

More particularly, the electron-attracting unit can be selected fromhalogen atoms, preferably light halogen atoms and, in particular,chlorine and fluorine. When p is 1, the corresponding substance RfH is ahaloform.

GEA can also be selected advantageously from nitrile, carbonyl,sulphonyl and perfluoroalkyl groups.

Preferred substances of formula RfH of this type which can be usedcorrespond to the formula

R—G—CF₂—H

where G represents a divalent group of formula —Z—G′— in which

the divalent Z represents a single bond, a chalcogen atom, or a divalentradical —Y(R′)— in which R′ is a hydrocarbon radical of not more thanten carbon atoms, advantageously not more than six carbon atoms, moreadvantageously not more than two carbon atoms, and Y is a metalloid atomof Group V (nitrogen, phosphorus, etc);

G′ represents >C═O, >S═O, —SO₂—, or —(CF₂)_(n)— in which n is an integergreater than or equal to 1;

and in which R represents an inert inorganic or organic residue,preferably an organic radical such as aryl or alkyl, including aralkyl,which is optionally substituted. R can also represent a solid, organicor inorganic support, such as a resin;

or else the unit R—G represents a nitrile, ester or amide(advantageously not bearing hydrogen) group, including sulphamide.

If G represents a perfluoroalkylene group —(CF₂)_(n)—, n isadvantageously between 1 and 10, preferably between 1 and 5. In thiscase, furthermore, R can also represent a halogen atom, especiallyfluorine.

Therefore, in an advantageous embodiment of the present invention, thesaid substance of formula RfH corresponds to the formula II in which GEArepresents an electron-attracting group of formula III:

R—C_(n)X′_(2n)—  (III)

in which n is an integer of not more than 5,

R is selected from hydrogen, a hydrocarbon radical, such as aryls andalkyls of 1 to 10 carbon atoms, and light halogens (chlorine orfluorine, advantageously fluorine),

and the radicals X′, which are identical or different, represent a lighthalogen (chlorine or fluorine, advantageously fluorine) or a radical offormula C_(m)F_(2m+1) in which m is an integer of not more than 5,preferably not more than 2.

When R represents a hydrogen, the reaction is more complex since thesaid substance is able to react at more than one site, and the ratiosbetween the reactants must take account of this reactivity in thestoichiometry. This polyvalent nature of the substances can be adisadvantage, and for this reason it is usually not desirable for R tobe hydrogen.

It is desirable for at least three quarters, advantageously at leastnine tenths, and preferably all, with the possible exception of one, ofthe radicals X and X′ to be fluorines or perfluoroalkyls (that is,strictly speaking, of the general formula of type C_(v)F_(2v+1)).

According to the present invention, the said substrate is advantageouslya compound of type:

in which Y is as defined above,

R₁ is a radical selected from hydrogen, hydrocarbon radicals such asaryl (including alkylaryl) and alkyl (including arylalkyl andcycloalkyl)

and R₂ is a radical selected from hydrocarbon radicals such as aryl(including alkylaryl) and alkyl (including aralkyl and cycloalkyl) andfrom amine functions which are advantageously persubstituted (in otherwords, whose nitrogen no longer carries a hydrogen), acyloxy functions,and hydrocarbyloxy functions, with the proviso that, when R₁ ishydrogen, R₂ is neither phenyl nor dimethylamino.

These chains R₁ and R₂ can be linked to one another to form one or morerings. Advantageously, the substituents are such that the sum of thecarbons present in the molecule is not more than approximately 50,preferably 30. It is desirable for one, and advantageously both, of R₁and R₂ not to be bulky; in other words, the atom connecting the saidradical to the said function >C═Y does not itself carry more than twochains (secondary radical), preferably not more than one chain (primaryradical).

R₁ and R₂ can be a secondary amine radical (dialkylamino), and in thiscase a significant increase is observed in the life expectancy of theunit denoted by Rf⁻. However, the tetrahedral complex is too temporaryto be used as a reagent over time as it is, and must be prepared insitu. It does not exist, like the other tetrahedral complexes of thehemiaminal type, or at least has not been able to be detected, in thepresence of a substrate of the ketone or aldehyde type.

The tetrahedral complexes, including those corresponding to DMF, canalso be obtained by the action of a [lacuna] on a radical of formulaRf—(R₁)(R₂)—C—O—Z′ in which Z′ is selected from hydrogen (in that case,the formula corresponds to a hemiaminal when, as is preferred, R₂ is aradical selected from amine functions) and —Si(R′)₃, in which theradicals R′ are identical or different and are hydrocarbon radicals of 1to approximately 20 carbon atoms, advantageously 1 to 10 and,preferably, 1 to 5, the total carbon number of Rf—Si(R′)₃ beingadvantageously not more than 50, preferably not more than 30. The saidbase is advantageously silicophilic, especially when Z′ is silyl.

When Z is H and forms a hemiaminal, the latter is advantageouslyobtained by the action of a secondary amine on the aldehyde of formulaRf—CHO with dehydration.

The said dehydration is preferably carried out by (hetero)azeotropicdistillation of water (diluent (for example toluene) or amine itself[for example, in the case of dibutylamine]). It can also be carried outwith a dehydrating agent.

Equally, although there have been numerous recommendations to useelements from Group VIII of the Periodic Table of the Elements withperfluoroalkylating agents in order to give favour to certain substratesand to promote certain types of reaction, this has not proved to beparticularly useful for the abovementioned reaction. For this reason, itis preferable to use reagents which do not comprise Group VIII metals,especially metals of the platinum group, which is the group consistingof platinum, osmium, iridium, palladium, rhodium and ruthenium.

In the present description, reference is made to the supplement toBulletin de la Société Chimique de France, No. 1, January 1966, in whicha periodic table of the elements was published.

Thus it is preferable for the level of metals of the platinum group, andeven of metals of Group VIII, to be less than 100 ppm, advantageouslyless than 10 ppm and, preferably, 1 ppm. These values relate to theinitial base and are expressed in moles.

More generally and more empirically, it can be indicated that it isdesirable for these two categories of metal, namely the transitionelements having two valence states and the elements of Group VIII, to beeach present in the reagent at an overall concentration which is notmore than 1000 molar ppm, preferably not more than 10 molar ppm.

It will be noted that the various metals present at such an overallconcentration are present in an extremely low amount and, in thisregard, they fulfil no catalytic role at all. Their presence does notimprove the kinetics of the reaction and may even be detrimental to itif they are present in too great an amount.

Except in the presence of silylating agent, where it plays the part of abase (see above), the use, in addition to components of abovementionedreagents, of alkali metal fluoride or of quaternary phosphonium fluoride[or even quaternary ammonium fluoride if one bears in mind theconstraints which this type of compound imposes], which are commonlypresent in the reagent systems utilizing fluorinated carboxylates, hasnot been found to be detrimental but has been found to be generally oflittle interest, especially in view of the fact that it produces salineeffluents which are difficult to treat. For this reason, it ispreferable to limit the level of such compounds, especially theirinitial level. Thus it is preferable for the fluoride content, moreprecisely the ionic fluoride content—that is to say, the fluoridecapable of being ionized in the polarizing medium of the reagent—to benot more than the initial molar concentration in the said material RfH,advantageously not more than half and, preferably, not more than aquarter.

When the substrate is sensitive to base degradation, it is appropriateto limit the amount of the latter, and especially the excess; therefore,where the substrates are susceptible to dismutation, as is the case withthe aldehydes, which may give rise to Cannizaro reactions and/orTishchenko reactions, or crotonization reactions, it is appropriate tolimit the amount of base to {fraction (4/3)}, advantageously to{fraction (5/4)}, preferably to 1.1, of the SA (i.e., the stoichiometricamount) in relation to the substrate.

The use of a substrate which is not sensitive to base degradationtherefore makes it possible to employ large excesses of base andtherefore of reagent. In this case an excess of from 20 to 300% ispossible; however, it is preferable to limit it, on grounds of cost, ingeneral, to a level of approximately 100%. Of course, the same valuesare applicable as when the substrate is sensitive to bases.

When the substrate also plays the part of a solvent, it is possible touse much smaller amounts of base (cf. hereinbelow).

The reaction is generally conducted at a temperature between the meltingpoint of the medium and the boiling point under the pressure conditionsof the reaction.

More specifically, the reaction is conducted in liquid phase at atemperature between approximately −100° C. and 0° C., advantageouslybetween approximately −60° C. and −10° C. When RfH is highly volatile itis preferable to ensure that there is no evaporation; for this purposeit is appropriate either to avoid too great a distance between thereaction temperature and the boiling point—more precisely, it isdesirable to operate at a temperature which is not greater than theboiling point (under atmospheric pressure) by more than 100° C. (twosignificant figures), advantageously by more than 80° C.—or to operatein a closed reactor, or else to operate under a high partial pressure ofthe said RfH. An alternative is to operate by the Grignard technique. Itis possible and, indeed, advantageous to combine at least two of theabove measures.

Finally, when the formation of carbene is promoted by the temperature,this formation of carbene is correlated with the evolution of hydrohalicacid, which promotes the secondary reactions. For this reason, it ispreferable to avoid operating at temperatures of not more than ambienttemperature (20° C.), preferably a temperature of at most −20° C., whensuch a risk exists (essentially when the carbon number of RfH is 1 orwhen GEA and/or X is a chlorine).

When the substrate is sensitive to base degradation it is likewisepreferable to operate at a temperature no higher than ambienttemperature. If there is the twin risk of carbene formation andsensitivity of the substrate to base, it is preferable not to exceedapproximately −20° C.

In a particularly advantageous embodiment of the present invention, thereaction is conducted such that either the substance RfH or the base isintroduced first in the medium, followed finally by the substrate. Inother words, a reagent is formed from the substance RfH, the base and,if appropriate, the solvent and/or diluent, and then this reagent isreacted with the substrate. This variant will be designated hereinbelowby the expression Grignard variant.

The reaction is conducted such that the final component of the reagentis introduced gradually and, advantageously, within a period of time ofbetween 5 and 300 minutes.

The reaction is conducted such that the said base is introducedgradually and, advantageously, over a period of time of between 5 and300 minutes.

Thus, in the course of the study which led to the present invention, itwas shown that the reagent led to a novel species

This species,

M⁺, has not been described anywhere as far as the Applicant is aware.Consequently, a major feature of the reagent according to the presentinvention is the presence of the said species (or of a pluralitythereof) in the reagent, advantageously at concentrations which will beset out below for the amide derivatives.

The present invention therefore relates to the compounds of formula:

In this formula, M⁺ represents a cation which is advantageouslymonovalent and which corresponds to the bases specified in the presentdescription; advantageously the alkali metals and the phosphoniums. Thepreferences for Rf, R₁ and R₂ are set out below for the amidederivatives, R₁ corresponding to R₁₃.

This tetrahedral intermediate compound can be used as aperfluoroalkylating reagent, as described above, but can also constitutea reaction intermediate which leads to advantageous compounds other thanthose obtained from the hydrolysis. The tetrahedral form can, inparticular, be blocked with known (essentially electrophilic) agents inorder to undergo addition with alkoxides to give, in particular, O-silylderivatives, O-acyl derivatives and (bi)sulphite derivatives. Theseblocked derivatives are particularly advantageous synthesisintermediates and reagents.

When it is used as a perfluoroalkylating reagent, it is preferable forthe substituents R₁, R₂ and, if appropriate, that of Y to be small insize; in other words, when they are alkyls, their carbon number isadvantageously not more than 6, advantageously not more than 3, and theyare preferably methyl; when they are aryls, advantageously phenyls(substituted or otherwise), it is preferable for their carbon number tobe, advantageously, not more than 10, advantageously not more than 8. Itis preferable for the radicals R₁, R₂ and Y to have a total carbonnumber of not more than 15, advantageously not more than 12 and,preferably, not more than 8.

When it is used not as a perfluoroalkylating reagent but as a synthesisintermediate, the radicals R₁, R₂ and Y can be greater in size (providedthat it is at least partly and preferably completely soluble in themedium), and in this case the total carbon number can reachapproximately 50. However, it is preferable not to go beyondapproximately 30 carbon atoms.

When they are employed, the amides used play a part in the formation ofthe reagent. It has in fact been demonstrated that the reagent formed inamides (especially when they correspond to the precursor of the formulaof the tetrahedral compound below) is a reagent whose reactive speciesis the addition compound of CF₃ ⁻ with the carbon of the carbonylfunction, the oxygen of the said function becoming anionic.

It is this compound which plays the part of the carrier of CF₃ ⁻ or,more precisely, of Rf⁻ according to the present invention; the compoundsof formula V can also be obtained by the following routes: addition ofan amine onto the fluoral hydrate or fluoral (in the following tworeaction equations, CF₃ is the paradigm of Rf):

followed by anionization using a base, for example of the type to whichthe present specification relates. However, these bases can also berelatively weak bases.

The operating conditions are advantageously the same as those for thetechnique which has just been set out above; however, the presence ofamide, although desirable, is not mandatory.

The amines can be of type R₂NH or RNH₂ (R=simple aryl or alkyl,corresponding to R₁₁ and/or R₁₂ in the formula IV); this method hasnever been described.

According to another possible route, it is possible to use thederivatives of type Rf—Si—(R)₃ in the presence of a base, whose anioncan be silicophilic. The tetrahedral anion obtained is itselfsilicophilic [lacuna] the base can be present in a catalytic amount(advantageously from {fraction (1/50)} to ½, preferably from {fraction(1/20)} to ⅓, of the SA (i.e., the stoichiometric amount)). The reactioncan be written using, as examples, CF₃SiEt₃ and formamide, and a(quaternary ammonium) fluoride as silicophile. It should be noted thatthis technique overcomes some disadvantages of the use of quaternaryammoniums.

Thus this process consists in reacting a compound of formula Rf—Si(R′)₃with a base whose anion is silicophilic, where the radicals R′ areidentical or different and are hydrocarbon radicals of 1 toapproximately 20 carbon atoms, advantageously 1 to 10 and, preferably, 1to 5, the total carbon number of Rf—Si(R′)₃ being advantageously notmore than 50, preferably not more than 30.

The term silicophile is understood to mean bases which are capable offorming a bond with a silyl having an energy of at least 110 kcal permol, advantageously an energy of approximately 120 and, preferably, 130(cf. R. Walsh, Acc. Chem. Res.).

According to an advantageous embodiment of the present invention, thecompound of formula V and in particular formula IV, can be obtained byreacting a base (advantageously a silicophilic base when R₂₀ is silyl)with a compound of formula R₁R₂RfC—Y—R₂₀ in which R₂₀ is a radicaladvantageously of not more than about 10 carbons and is selected fromsilyls and acyls;

Y represents a nitrogen, advantageously a substituted nitrogen, or a achalcogen atom;

R₁ is a radical selected from hydrogen and hydrocarbon radicals such asaryl and alkyl;

and R₂ is a radical selected from hydrocarbon radicals such as aryl andalkyl, amine functions, which advantageously are persubstituted, acyloxyfunctions and hydrocarbyloxy functions.

The presence of this species in the reagent is a further importantfeature of the said novel reagent. The present invention also relates inparticular to the compounds of formula (IV)Rf—C[O⁻(M⁺)][R₁₃][NR₁₁)(R₁₂)] and to the reagents which comprise atleast one such compound

Of course, the above formula is also intended to embrace the otherenantiomer.

This intermediate can be identified by fluorine NMR (in the case ofdimethylformamide, δ of approximately 1 ppm [difficult-to-resolvedoublet] relative to HCF₃).

In this formula, M⁺ represents a cation which is advantageouslymonovalent and which corresponds to the bases specified in the presentdescription;

advantageously, alkali metals and phosphoniums.

Rf is as defined above, R₁₁, R₁₂ and R₁₃ represent aryl, includingalkylaryl, and alkyl, including aralkyl and cycloalkyl, hydrocarbonchains, it being possible for these chains to be linked to one anotherto form one or more rings. R₁₃ has a Hammett constant which is lower interms of its absolute value than 0.2, preferably than 0.1.

Alternatively, R₁₃ can be hydrogen, which is its preferred definition.Another satisfactory definition of R₁₃ is aryl, whose Hammett constantis advantageously lower in terms of its absolute value than 0.2,preferably than 0.1.

This intermediate possesses a good stability, especially at lowtemperatures (for example −10° C., advantageously −20° C., preferably−30° C.).

The present invention therefore relates to a reagent of the above typewhich comprises at least one compound of formula IV in a concentrationof not less than one millimole per liter, advantageously not less than 5millimoles per liter and, preferably, 10 millimoles per liter.

This intermediate can be used as a perfluoroalkylating reagent asdescribed below but may also constitute a reaction intermediate whichleads to advantageous compounds, especially aldehydes and O-silyl,O-acyl and (bi)sulphite derivatives.

When it is used as perfluoroalkylating reagent, it is preferable for theradicals R₁₁, R₁₂ and R₁₃ to be small in size; in other words, when theyare alkyls, their carbon number should advantageously be not more than6, advantageously not more than 3, and they should preferably bemethyls; when they are aryls, advantageously phenyls (substituted orotherwise), it is preferable for their carbon number to beadvantageously not more than 10, advantageously not more than 8. It ispreferable for the radicals R₁₁, R₁₂ and R₁₃ in total to have a carbonnumber of not more 15, advantageously not more than 12 and, preferably,not more than 8.

When it is used not as a perfluoroalkylating agent but as a synthesisintermediate, the radicals R₁₁, R₁₂ and R₁₃ can be greater in size(provided that it is soluble in the medium), and in this case the totalcarbon number can reach approximately 50. However, it is preferable notto go beyond approximately 30 carbon atoms.

It is therefore highly recommendable to use, alone or in a mixture(optionally with other amides) the amides of formula R₁₃—CO—N(R₁₁)(R₁₂),the recommended ratio between these amides and the base that is usedbeing in this case at least 1, advantageously at least 2 and,preferably, at least 5. There is no upper limit except when it (they)constitutes (constitute) the totality of the polar solvent. When theseamides are used as solvents, in the tests carried out it is most oftenthe case (without this necessarily being an optimum) that the proportionof the said amides relative to the sum of the polar solvents is betweenapproximately 40 and 80%.

Considering the solvents, it is therefore preferable to use, as thepolar aprotic solvent, those which have a significant dipole moment.Therefore, the relative dielectric constant ∈ of the solvent isadvantageously at least equal to approximately 5. Preferably, ∈ is lessthan or equal to 50 (the positional zeros are not considered to besignificant figures in the present description unless specifiedotherwise) and greater than or equal to 5.

It is preferred, moreover, for the solvents of the invention to becapable of solvating the cations well (which is often related to thebasicity of the solvent), a quantity which can be codified by the donorindex D of these solvents. It is therefore preferable for the donorindex D of these solvents to be between 10 and 30.

In relation to the requirements relating to the basicity of the organicsolvent to be employed, it will be recalled that the donor index ordonor number is sometimes designated in the abbreviated form “DN” andgives an indication of the nucleophilic nature of the solvent and showsits aptitude to give its doublet.

In the work by Christian Reinhardt [Solvents and Solvent Effects inOrganic Chemistry—VCH p. 19 (1988)], a definition is given of the donornumber, which is defined as the negative (−ΔH) of the enthalpy(kcal/mol) of the interaction between the solvent and antimonypentachloride in a dilute solution of dichloroethane.

According to the present invention, it is preferable for the reagent tohave no acidic hydrogen on the polar solvent or solvents which it uses.Especially when the polar nature of the solvent or solvents is obtainedby the presence of electron-attracting groups, it is desirable for thereto be no hydrogen in the alpha position of the electron-attractingfunction.

More generally, it is preferable for the pK_(a) corresponding to theprimary acidity of the solvent to be at least approximately 20(“approximately” emphasizing the fact that only the first figure issignificant), advantageously at least 25 and, preferably, between 25 and35.

It is preferable for the components of the reaction medium, especiallythe said base and in particular the said substance R_(f)H, to be atleast partially and, preferably, completely soluble in the medium whichconstitutes the reagent.

Solvents which give good results can in particular be solvents of theamide type. The amides include amides having a special nature, such astetrasubstituted ureas and monosubstituted lactams. The amides are,preferably, substituted (disubstituted in the case of ordinary amides).Mention may be made, for example, of pyrrolidone derivatives, such asN-methylpyrrolidone, or else N,N-dimethylformamide orN,N-dimethylacetamide.

Another particularly interesting category of solvents consists of theethers, either symmetrical or asymmetrical and either open or otherwise.The category of the ethers must be understood as incorporating thevarious derivatives of the glycol ethers, such as the various glymes:diglyme for example.

Therefore the most suitable solvents, owing to their price and theirproperties, are advantageously selected from ethers, especially cyclicethers, such as THF, or polyfunctional ethers, such as glymes, and thoseof the amides which, like DMF or the DAAUs (N,N′-dialkylalkyleneureas)such as DMEU (N,N′-di-methylethyleneurea) or DMPU(N,N′-dimethylpropyleneurea), have no acidic hydrogen. Basicheterocycles, such as pyridine, can be used, although they do notconstitute a class of preferred solvents.

Among the diluents, mention may be made of aliphatic or aromatichydrocarbons, such as alkanes, or aryl derivatives. Mention must be madeof the arylmethanes, which may be used both as diluent (since they areinert under the reaction conditions) and as sources of base when thelatter is prepared beforehand in situ.

The use of this reagent as a perhaloalkylating agent takes place simplyby adding the said reagent to the target substrate or vice versa, theamide derivatives having been found to date to constitute the bestreagents (formula IV).

The target substrates are advantageously selected from those which carryat least one electrophilic function by addition. In other words, thereaction takes place, in any case transitorily, by addition onto afunction which has a double bond (including of course that of thedonor-acceptor type) or a doublet belonging to a metalloid whose rankingperiod is at least equal to 3.

Therefore, according to a particularly advantageous embodiment of thepresent invention, such an electrophilic function by addition isselected from the following functions: carbonyl, thiocarbonyl (>C═S),optionally conjugated with one or more bonds of ethylenic type,chalcogenides (in which the atomic ranking of the chalcogen is at leastequal to that of sulphur) carrying a good leaving group (see above) and,in particular, dichalcogenides (in which the atomic rankings of thechalcogens are at least equal to that of sulphur). It should be notedthat the reaction is penalized when the chalcogen carries a bulkyradical (a secondary radical, and especially a tertiary radical) and/ora radical whose carbocation is stabilized (a radical of the benzyl ortert-alkyl type).

Thus the reagent reacts with equal advantage with a compound selectedfrom carbonyl compounds of the ketone, aldehyde or activated ester type(or even acid halide) by carrying out an addition onto the carbonylfunction. The product of the reaction is an alcohol or alkoxide in whichthe carbon atom carrying the hydroxyl function is substituted by asubstituted difluoromethyl group. These intermediate alkoxides,following hydrolysis (generally acidic hydrolysis), give thesubstitution or addition compound. The case of the amides is developedin the passage relating to the tetrahedral intermediate.

When the electrophilic function of the substrate carries with it therisk of giving transesterification-type reactions with the base, it isdesirable for the basicity of the leaving group to be similar to orgreater than that of the base initially introduced as reagent.

The reaction is advantageously conducted at a temperature similar andunder conditions similar to those of the formation of the reagent.

The present invention also relates to the compounds of formula:

R₁R₂RfC—Y—R₂₀

in which R₂₀ is a radical, advantageously of not more than about 10carbons, selected from akyls, silyls, acyls and that corresponding tothe bisulphite combination;

Y represents a nitrogen, advantageously a substituted nitrogen, or achalcogen atom;

R₁ is a radical selected from hydrogen and hydrocarbon radicals such asaryl and alkyl; and

R₂ is a radical selected from hydrogen, hydrocarbon radicals such asaryl and alkyl, amine functions, which are advantageouslypersubstituted, acyloxy functions and hydrocarbyloxy functions, with theproviso that, if R₁ is hydrogen, R₂ is phenyl or dimethylamino and Rfcontains only one carbon, R₂ cannot be silyl of less than 10 carbons;

or, more restrictively, with the proviso that, if R₁ is hydrogen, R₂ isneither phenyl nor dimethylamino, or with the proviso that, if Rfcontains only one carbon, R₂ cannot be silyl of less than 10 carbons.

The above compounds (including those which have been renouncedadvantageously) are also useful (when R₂₀O⁻ is a good leaving group) forforming a Vilsmeyer salt (CF₃CH═N⁺Me₂, in general with the said leavinggroup R₂₀O⁻ as counteranion).

Considered as good leaving groups in the present description are thecompounds of the pseudohalogen type, i.e., a radical (in general, thisradical possesses a light chalcogen (sulphur or, preferably, oxygen) viawhich it is linked to the remainder of the molecule) which, in leaving,forms an anion whose associated acid has an acidity (measured by theHammett constant) at least equal to that of acetic acid. Among typicalpseudohalogens mention may be made of the acyloxyradicals correspondingto the acids perhalogenated alpha to the acyloxy function, such astrifluoroacetyloxy (CF₃—CO—O—) and especially sulphonyloxy radicals,above all those whose sulphur-carrying carbon is perfluorinated and ofwhich the paradigm is trifluoromethylsulphonyloxy (CF₃—SO₂—O—).

For the present invention, preference will be given to those of thepseudohalogens which, in leaving, have an acidity which is at leastequal to that of the sulphonic acids, such as tosylic acid (a paradigmof the arylsulphonic acids) or mesylic acid (a paradigm of thealkylsulphonic acids).

General procedure used in particular for the examples

ABBREVIATIONS

cata: catalytic

CDCl₃: deuterated chloroform

CFCl₃: trichlorofluoromethane

ClSiMe₃: trimethylsilyl chloride

CsF: caesium fluoride

DMEU: N,N′-dimethylethyleneurea

DMF: dimethylformamide

DMPU: N,N′-dimethylpropyleneurea

eq: equivalent

HCF₃: fluoroform

HCl: hydrochloric acid

HMDZ: hexamethyldisilazane

LiN(SiMe₃)₂: lithium bis(trimethylsilyl)amide

M: molarity

Me₄NF: tetramethylammmonium fluoride

mmol: millimole

N(SiMe₃)₃: tris(trimethylsilyl)amine

Qty: quantity

TBAF.3H₂O: tetrabutylammonium fluoride trihydrate

TBAT: tetrabutylammonium difluorotriphenylsilicate

tBuOK: potassium tert-butoxide

THF: tetrahydrofuran

Yld: yield

In the course of this study, various methods of addition of the reagentswere used. In an attempt at simplification, these various methods havebeen identified as follows:

Procedure A

In the case of the usual bases (for example, amides of type LiN(SiMe₃)₂or tBuOK), the base (generally 1M in THF) is added to afluoroform/electrophile/solvent mixture.

In the case of the system N(SiMe₃)₃/M⁺F⁻, the silylated amine, insolution in THF, is run into the fluoride/electrophile/solvent mixture.

Procedure C

This method of addition was used in particular for the action of thesystem of type N(SiMe₃)₃/F⁻ on base-sensitive substrates (cf.hereinabove) such as benzylic derivatives or enolizable ketones. Thesilylated amine/electrophile/solvent (in general, THF) solution is thenadded to the fluoride/fluoroform/solvent mixture.

General Notes

All of the reactions described were carried out under nitrogen.

All of the solvents and reactants are used in anhydrous form:

the dimethylformamide is distilled over CaH₂ and then stored over 4 Åmolecular sieve and under nitrogen.

the tetrahydrofuran is distilled over Na/benzophenone and then storedover 4 Å molecular sieve and under nitrogen.

The various components of the basic systems used are commercialproducts:

LiN(SiMe₃)₂ (1M in THF), 100 ml, ALDRICH

tBuOK (1M in THF), 50 ml, ALDRICH

N(SiMe₃)₃ 98%, 25 g, ALDRICH

anhydrous Me₄NF, 10 g, ACROS

TBAT 97%, 25 g, ALDRICH

Definition of the perfluoroalkylating system for thechalcogen-containing derivatives

In the case of all of the sulphur- or selenium-containing substrates, 2types of conditions were applied:

For 1 mmol of substrate

Rf in excess (of from 1.4 mmol to 8.6 mmol, or/HCF₃ from 200 mg to 600mg) LiN(SiMe₃)₂ (1M in THF) (1.1 ml or 1.1 mmol of base)/HMDZ (40 μl or0.2 mmol)/DMF (2 ml). Procedure A

(from 1.4 mmol to 8.6 mmol, or HCF₃ from 200 mg to 600 mg) persilylatedamine (1.5 mmol or N(SiMe₃)₃ 350 mg) in 1 ml of THF/silicophilic base(1.5 mmol Me₄NF or 140 mg)/DMF (2 ml) or THF (2 ml); Procedure A.

The following, non-limiting examples illustrate the invention.

EXAMPLE 1 Trifluoromethylation of Dichalcogenated Substrates

Procedure A

The model substrate chosen for the various modes of operation isdi-n-octyl disulphide.

Temperature range: −20° C. to 30° C.

Substrate concentration: 1 mmol in 3 ml.

Typical reaction: (C₈H₁₇S)₂/N(SiMe₃)₃/Me₄NF

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith di-n-octyl disulphide (291 mg, 1 mmol), anhydroustetramethylammonium fluoride (140 mg, 1.5 mmol) and then 2 ml ofanhydrous DMF. The reaction mixture is cooled to 0° C. and thenfluoroform (200 mg, 2.9 mmol) is bubbled in. A solution oftris(trimethylsilyl)amine (352 mg, 1.5 mmol) in 1 ml of THF issubsequently injected at 0° C. The reaction mixture is stirred at 0° C.for 5.5 h. It is then allowed to return to room temperature and isassayed by ¹⁹F NMR: the trifluoromethyl n-octyl sulphide is obtainedwith a crude yield of 76%.

Workup: The crude reaction mixture is admixed with water (2 ml) and 1Nhydrochloric acid (0.5 ml). The aqueous phase is extracted 3 times withethyl ether. The organic phases are combined, washed once with saturatedaqueous NaCl solution and twice with water, and then dried over Na₂SO₄.After filtration, the solvent is evaporated cold under reduced pressureto give a crude oil (306 mg). The purification of this oil on the silicacolumn (eluent: pure petroleum ether) makes it possible to isolatedi-n-octyl disulphide (37 mg), n-C₈H₁₇SH (88 mg) and trifluoromethyln-octyl sulphide (140 mg, 0.65 mmol, 65%).

The results are collated in the following table:

Base systems: I: LiN(SiMe₃)₂ (1.1 eq.)/HMDZ (0.2 eq.) II: N(SiMe₃)₃ (1.5eq.)/Me₄NF (1.5 eq.) III: tBuOK (1.1 eq.) Desired product YieldSubstrate obtained Base system (%)^(a)

I II II^(b) III 51 73 (65) 66 54 (34)

I II III 2^(c) 54 45

II 23

I II III 4^(e) 6 82 Ph-Se-Se-Ph Ph-Se-CF₃ N(SiMe₃)₃ (1.5 eq.)/ 61 (47)Me₄NF (1.5 eq.) Ph-Se-Se-Ph Ph-Se-CF₃ tBuOK (1.1 eq.) 77 ^(a)Yieldassayed by ¹⁹F NMR (isolated yield). ^(b)Use of THF as solvent.^(c)By-product: C₆H₁₁SCF₂H; Yield (¹⁹F) = 1%. ^(d)Addition according toprocedure C. ^(e)By-product: PhSCF₂H: Yield (¹⁹F) = 23%.

EXAMPLE 2 Trifluoromethylation of Thiocyanates

The trifluoromethylation of thiocyanates and selenocyanate is carriedout in dimethylformamide in the presence of an excess of fluoroform at alow temperature for two hours.

The two base systems used for these experiments were the pairingN(SiMe₃)₃/Me₄NF, on the one hand, and tBuOK, used by way of comparison,on the other.

Substrate Base system Yield (%)^(a) CH₃(CH₂)₇— N(SiMe₃)₃ (1.5 eq.)/Me₄NF(1.5 eq.) 40 N(SiMe₃)₃ (1.5 eq.)/Me₄NF (1.5 eq.)^(b) 11 N(SiMe₃)₃ (1.5eq.)/Me₄NF (0.2 eq.)  5 tBuOK (1.1 eq.)

N(SiMe₃)₃ (1.5 eq.)/Me₄NF (1.5 eq.) tBuOK (1.1 eq.) 25 46

N(SiMe₃)₃ (1.5 eq.)/Me₄NF (1.5 eq.) tBuOK (1.1 eq.) 23 (28)^(b) 24

EXAMPLE 3 Trifluoromethylation of Selenocyanates

TRIFLUOROMETHYLATION OF CARBONYL DERIVATIVES BY HCF₃

Definition of the Trifluoromethylating System

In the case of the carbonyl derivatives, the choice oftrifluoromethylating conditions depends on the base-sensitivity of thesubstrate.

Base-insensitive Substrates

For 1 mmol of substrate

HCF₃ (from 200 mg to 600 mg, or from 1.4 mmol to 8.6 mmol)/LiN(SiMe₃)₂(1M in THF) (1.1 ml, or 1.1 mmol of base)/HMDZ (40 μl, or 0.2 mmol)/DMF(2 ml). Procedure A.

HCF₃ (from 200 mg to 600 mg, or from 1.4 mmol to 8.6 mmol)/N(SiMe₃)₃(350 mg, or 1.5 mmol) in 1 ml of THF/F⁻ (from 0.2 to 1.5 mmol).Procedure A.

Nature of F⁻:

Me₄NF (from 19 mg to 140 mg)/DMF (2 ml) or DMEU (2 ml) or DMPU (2 ml).

Me₄NF (idem)/cata. DMF (25 μl, or 0.3 mmol)/THF (2 ml).

CsF (from 25 mg to 230 mg)/DMF (2 ml).

TBAT (from 111 mg to 835 mg)/DMF (2 ml).

TBAT (idem)/cata. DMF (25 μl, or 0.3 mmol)/THF (2 ml).

TBAT (idem)/THF (2 ml).

Enolizable Ketones

In this case, a single trifluoromethylating system makes it possible toobtain the trifluoromethylated alcohols:

For 1 mmol of substrate

HCF₃ (from 200 mg to 600 mg, or from 1.4 mmol to 8.6 mmol)/N(SiMe₃)₃(350 mg, or 1.5 mmol) in 1 ml of THF/Me₄NF (140 mg, or 1.5 mmol)/DMF (2ml). Procedure C.

EXAMPLE 4 Non-enolizable Ketones

Example using Me₄NF as fluoride

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith benzophenone (183 mg, 1 mmol), anhydrous tetramethylammoniumfluoride (22 mg, 0.24 mmol), 2 ml of THF, and then dimethylformamide (25μl, 0.3 mmol). The reaction mixture is cooled to −10° C. and thenfluoroform (400 mg, 5.7 mmol) is bubbled in. A solution oftris(trimethylsilyl)amine (348 mg, 1.5 mmol) in 1 ml of THF issubsequently injected at −10° C. The reaction mixture is stirred at −10°C. for 1 h. It is then allowed to return to room temperature and isassayed by ¹⁹F NMR: the silylated trifluoromethylcarbinol and thetrifluoromethylated alkoxide are obtained with crude yields of 38% and52% respectively.

Workup: the crude reaction mixture is admixed with water (2 ml) and 1Nhydrochloric acid (0.5 ml). The aqueous phase is extracted 3 times withethyl ether. The organic phases are combined, washed once with saturatedaqueous NaCl solution and twice with water, and then dried over Na₂SO₄.Following filtration, the solvent is evaporated cold under reducedpressure to give a crude oil (311 mg). Purification on a silica column(eluent: petroleum ether/acetone=7/1) makes it possible to isolatebenzophenone (32 mg),1,1-diphenyl-1-(trimethylsilyloxy)-2,2,2-trifluoroethanol (194 mg, 0.6mmol, 60%) and 1,1-diphenyl-2,2,2-trifluoroethanol (18 mg, 0.07 mmol,7%).

: PhCOPh/LiN(SiMe₃)₂/HMDZ

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith benzophenone (181 mg, 1 mmol) and then 2 ml of anhydrous DMF. Thereaction mixture is cooled to −15° C. and then fluoroform (300 mg, 4.3mmol) is bubbled in. Hexamethyldisilazane (50 μl, 0.24 mmol) and thenLiN(SiMe₃)₂ (1.1 ml, 1.1 mmol) are subsequently injected in successionat −15° C. The reaction mixture is stirred at −15° C. for 1 h. It isthen allowed to return to room temperature and is assayed by ¹⁹F NMR:the silylated trifluoromethylcarbinol and the trifluoromethylatedalkoxide are formed with crude yields of 2% and 19% respectively.

Workup is exactly the same as above.

General conditions (with exceptions indicated in the table)

R₁ R₂ Base System R₃ Yield^(a) Remarks Ph Ph LiN(SiMe₃)₂ (1.1 eq.)/HMDZ(0.2 eq.) H/SiMe₃ 19/2 THF N(SiMe₃)₃ (1.5 eq.)/Me₄NF (1.5 eq.) H 72 (50)solvent = THF + N(SiMe₃)₃ (1.5 eq.)/Me₄NF (0.2 eq.) H/SiMe₃ 57/28(47/33) 0.3 eq. of DMF N(SiMe₃)₃ (0.2 eq.)/Me₄NF (0.2 eq.) H 6 in THFN(SiMe₃)₃ (1.5 eq.)/CsF (0.2 eq.) H/SiMe₃ 37/66 (18/68) N(SiMe₃)₃ (1.5eq.)/TBAT (0.2 eq.) H/SiMe₃ 69/40 (69/30) N(SiMe₃)₃ (1.5 eq.)/TBAT (0.2eq.) H 71 N(SiMe₃)₃ (1.5 eq.)/TBAT (0.2 eq.) H/SiMe₃ 91/3 (36/55)N(SiMe₃)₃ (1.5 eq.)/TBAF.3H₂O (0.2 eq.) H 5 tBuOK (1.1 eq.) H 100 (76)tBuOK (1.1 eq.) H 67

Ph N(SiMe₃)₃ (1.5 eq.)/Me₄NF (1.5 eq.) (SiMe₃)₃ (1.5 eq.)/Me₄NF (0.2eq.) H H/SiMe₃ 30 (40) 68 (42/26)

N(SiMe₃)₃ (1.5 eq.)/Me₄NF (0.2 eq.) H/SiMe₃ 40/22 (45) d) Yield ofalcohol silylated by ClSiMe₃ 4-F—C₆H₄— 4-F—C₆H₄— N(SiMe₃)₃ (1.5 eq.)/CsF(0.2 eq.) H/SiMe₃ 43/44 (0/64)

N(SiMe₃)₃ (1.5 eq.)/CsF (0.2 eq.) SiMe₃ 72 (57) DC = 62% ^(a)Yieldassayed by ¹⁹F NMR (and isolated yield).(%)

EXAMPLE 5 Non-enolizable Ketones. Solvent Effect

Procedure A R₁ R₂ Solvent R₃ Yield (%)^(a)

DMF THF + DMF (0.3 eq.) DMEU DMPU H/SiMe₃ H/SiMe₃ H/SiMe₃ H/SiMe₃ 80/1052/38 (7/60) 41/34 51/16

DMF THF + DMF (0.3 eq.) H/SiMe₃ H/SiMe₃ 68/0 (42/26) 17/2

DMF H/SiMe₃ ⁻ 40/22 (45)^(b)

THF + DMF (0.3 eq.) SiMe₃ 83 (75)^(d) ^(a)Yield assayed by ¹⁹F NMR(isolated yield). ^(b)Yield of silylated alcohol after treatment withClSiMe₃ (1 eq.). ^(d)Recovery of 19% of fluorenone.

EXAMPLE 6 Non-enolizable Ketones. Case of Quinols

The operating conditions employed are those used in the case of theketones, with the final hydrolysis being carried out in a neutral oracidic medium.

Post-reaction workup in a neutral medium:

1) N(SiMe₃)₃ (1.5 eq.)/Me₄NF (0.2 eq.) in DMF at −10° C. for 1 hour(Procedure A). 2) H₂O.

Between parentheses: yield of isolated product.

Aqueous treatment in a neutral medium and chromatography on silica givethe trifluoromethylated alcohol 2 (45%) and the ketone 1 obtained fromthe hydrolysis of the ketal function of 2 (22%).

Post-reaction workup in an acidic medium:

Between parentheses: yield of isolated product.

If workup is carried out in an acidic medium (1N HCl), with thetrifluoromethylation reaction being carried out under identicalconditions, the ketone 3 is obtained with a yield of 44% afterchromatography on silica.

Trifluoromethylation of quinols of the 4-methoxy-4-methylcyclohexa-2,5-dien-1-one type

R₁ R₂ Base system R Yield (%)^(a) ¹⁹F NMR^(b) H H N(SiMe₃) (1.5 eq.)SiMe₃ 64 (44)^(c)} 26 −81.23 Me₄NF (0.2 eq.) H d.e. = 0%} 38 −81.90tBuOK (1.1 eq.) 26 (42) −80.64 33 (33) −81.27 tBu H N(SiMe₃) (1.5 eq.)SiMe₃ 52 (43)^(c)} 8 −72.58 TBAT (0.2 eq.) d.e. = 60%} 44 −75.24^(a)Yields of 2 stereoisomers assayed by ¹⁹F NMR (isolated yield).^(b)In CDCl₃, ppm (ref.: CFCl₃). ^(c)Isolated yield corresponding to themixture of the two stereoisomers.

EXAMPLE 7 Enolizable Ketones

General conditions (with exceptions indicated in Table 8)

Procedure C:

The model substrate chosen for the various methods of operation isacetophenone.

Temperature range: −20° C. to 30° C.

Substrate concentration: 1 mmol in 3 ml. PhCOMe/N(SiMe₃)₃/Me₄NF

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith anhydrous tetramethylammonium fluoride (140 mg, 1.5 mmol) and 2 mlof anhydrous DMF. The mixture is cooled to −10° C. and then fluoroform(400 mg, 4.3 mmol) is bubbled in. A solution oftris(trimethylsilyl)amine (350 mg, 1.5 mmol) and acetophenone (120 mg, 1mmol) in 1 ml of THF is subsequently injected at −10° C. The reactionmixture is stirred at −10° C. for one hour. The mixture is allowed toreturn to room temperature and is assayed by ¹⁹F NMR: thetrifluoromethylated alkoxide is formed with a crude yield of 26%.

R₁ R₂ Base system R₃ Yield (%)^(a) Ph CH₃ ⁻ N(SiMe₃)₃ (1.5 eq.)/Me₄NF H26 (1.5 eq.) Ph CH₃CH₂ ⁻ N(SiMe₃)₃ (1.5 eq.)/Me₄NF H 28 (1.5 eq.) Ph2-CH₃—C₆H₅ N(SiMe₃)₃ (1.5 eq.)/Me₄NF H 11 (1.5 eq.)

N(SiMe₃)₃ (1.5 eq.)/Me₄NF (1.5 eq.) N(SiMe₃)₃ (1.5 eq.)/Me₄NF (0.2 eq.)H/SiMe_(3 H/SiMe) ₃ 36/14  3/42^(c) ^(a)Yield assayed by ¹⁹F NMR(isolated yield) c: After 10 days at room temperature.

In the case of enolizable ketone, procedure C and the use of Me₄NF givebest results. The aromatic nature of the ketone is not favourable to thesubstoichiometric use of silicophilic anions, and especially fluoride.

EXAMPLE 8 Trifluoromethylation of N-formyl Amides (DMF)

Procedure A

Temperature range: −20° C. to 30° C.

Substrate concentration: 1 mmol in 3 ml. DMF/N(SiMe₃)₃/TBAT

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith tetrabutylammonium difluorotriphenylsilicate (111 mg, 0.2 mmol) and2 ml of dimethylformamide. The reaction mixture is cooled to −10° C. andthen fluoroform (400 mg, 5.7 mmol) is bubbled in. A solution oftris(trimethylsilyl)amine (348 mg, 1.5 mmol) in 1 ml of THF issubsequently injected at −10° C. The reaction mixture is stirred at −10°C. for 1 h. It is then allowed to return to room temperature,chlorotrimethylsilane (130 μl, 1 mmol) is added, and the mixture isassayed by ¹⁹F NMR: the silylated tetrahedral intermediate is obtainedwith a crude yield of 27%.

EXAMPLE 9 Trifluoromethylation of N-formyl AmidesN-methylmorpholine/N(SiMe₃)₃/TBAT

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith N-methylmorpholine (117 mg, 1 mmol), tetrabutylammoniumdifluorotriphenylsilicate (110 mg, 0.2 mmol) and 2 ml of THF. Thereaction mixture is cooled to −10° C. and then fluoroform (400 mg, 5.7mmol) is bubbled in. A solution of tris(trimethylsilyl)amine (351 mg,1.5 mmol) in 1 ml of THF is subsequently injected at −10° C. Thereaction mixture is stirred at −10° C. for 1 h. It is allowed to returnto room temperature and is assayed by ¹⁹F NMR: the silylatedtrifluoromethylcarbinol and the trifluoromethylated alkoxide areobtained with crude yields of 49% and 15% respectively.Chlorotrimethylsilane (130 μl, 1 mmol) is then injected and the mixtureis left with stirring at room temperature for one hour.

Workup: the crude reaction mixture is admixed with water (2 ml). Theaqueous phase is extracted 3 times with ethyl ether. The organic phasesare combined, washed once with saturated aqueous NaCl solution and twicewith water, and then dried over Na₂SO₄. Following filtration, thesolvent is evaporated cold under reduced pressure to give a crude oil(534 mg). Purification on a silica column (eluent: petroleumether/acetone=9/1) makes it possible to isolate the silylatedtrifluoromethylated tetrahedral intermediate with a yield of 60%.

EXAMPLE 10 Trifluoromethylation of Phthalimides

Procedure A

The substrate is N-methylphthalimide.

Temperature range: −20° C. to 30° C.

Substrate concentration: 1 mmol in 3 ml.N-methylphthalimide/N(SiMe₃)₃/Me₄NF

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith N-methylphthalimide (160 mg, 1 mmol), anhydrous tetramethylammoniumfluoride (22 mg, 0.24 mmol) and 2 ml of DMF. The reaction mixture iscooled to −10° C. and then fluoroform (200 mg, 2.9 mmol) is bubbled in.A solution of tris(trimethylsilyl)amine (351 mg, 1.5 mmol) in 1 ml ofTHF is subsequently injected at −10° C. The reaction mixture is stirredat −10° C. for 1 h. It is then allowed to return to room temperature andis assayed by ¹⁹F NMR: the silylated trifluoromethylated alcohol isobtained with a crude yield of 7%.

Workup: The crude reaction mixture is admixed with water (2 ml) and 1Nhydrochloric acid (0.5 ml). The aqueous phase is extracted 3 times withethyl ether. The organic phases are combined, washed once with saturatedaqueous NaCl solution and twice with water, and then dried over Na₂SO₄.Following filtration, the solvent is evaporated cold under reducedpressure to give a crude oil (442 mg). Purification on a silica column(eluent: petroleum ether/ethyl ether=1/1) makes it possible to isolateN-methylphthalimide (130 mg) and the silylated trifluoromethylatedalcohol (37 mg, 0.14 mmol).

EXAMPLE 11 Use of Tetrahedral Intermediates

The model substrate chosen for the various methods of operation isbenzophenone.

Temperature range: −20° C. to 30° C.

Substrate concentration: 1 mmol in 3.5 ml.

EXAMPLE 12 DMF/N(SiMe₃)₃/TBAT/PhCOPh

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith tetrabutylammonium triphenyldifluorosilicate (111 mg, 0.2 mmol) and2 ml of dimethylformamide. The reaction mixture is cooled to −10° C. andthen fluoroform (400 mg, 5.7 mmol) is bubbled in. A solution oftris(trimethylsilyl)amine (348 mg, 1.5 mmol) in 1 ml of THF issubsequently injected at −10° C. The reaction mixture is stirred at −10°C. for 1 h. It is then allowed to return to room temperature and isassayed by ¹⁹F NMR: the trifluoromethylated tetrahedral intermediate inanionic and silylated form is obtained with respective crude yields of18% and 87% (yields calculated relative to benzophenone). A solution ofbenzophenone (182 mg, 1 mmol) in 0.5 ml of DMF is then injected. Thereaction mixture is stirred at room temperature for 24 h and thenassayed by ¹⁹F NMR: the silylated trifluoromethylcarbinol and thetrifluoromethylated alkoxide are obtained with crude yields of 21% and71% respectively. Following conventional workup and purification (cf.Example 17), 1,1-diphenyl-1-(trimethylsilyloxy)-2,2,2-trifluoroethanol(32 mg, 0.32 mmol, 10%) and 1,1-diphenyl-2,2,2-trifluoroethanol (219 mg,0.87 mmol, 87%) are isolated.

: N-methylmorpholine/N(SiMe₃)₃/TBAT/PhCOPh

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith tetrabutylammonium triphenyldifluorosilicate (111 mg, 0.2 mmol),N-methylmorpholine (117 mg, 1 mmol) and 2 ml of THF. The reactionmixture is cooled to −10° C. and then fluoroform (300 mg, 4.3 mmol) isbubbled in. A solution of tris(trimethylsilyl)amine (352 mg, 1.5 mmol)in 1 ml of THF is subsequently injected at −10° C. The reaction mixtureis stirred at −10° C. for 1 h. It is then allowed to return to roomtemperature and is assayed by ¹⁹F NMR: the trifluoromethylatedtetrahedral intermediate in its silylated form is obtained with a crudeyield of 37% (yield calculated relative to benzophenone). A solution ofbenzophenone (180 mg, 1 mmol) in 0.5 ml of THF is then injected. Thereaction mixture is stirred at room temperature for 24 h and thenassayed by ¹⁹F NMR: the trifluoromethylated alkoxide is obtained with acrude yield of 20%, but there remains 0.23 mmol of residual tetrahedralintermediate.

EXAMPLE 13 Deprotonation of Fluoroform by KN(SiMe₃)₂ and Silylation ofthe Tetrahedral Intermediate by a Silylating Agent

(1)/(2)/(3) RY(4) % R₄Si (b) (a) Me₃SiCl 4/1/1.1 48.5 tBuMe₂Si 4/1/1.1−55   Cl (Me₃Si)₃ 4/1/1.1 33.5 N (a) fluorine NMR assay with internalstandard (b) molar ratio REACTANTS Fluoroform 28 mmol (2 g) KHMDZ 7 mmolSilylating agent^((b)) 7.7 mmol Anhydrous DMF 30 ml ^((a))Silylatingagents tested: Me₃SiCl, (Me₃Si)₃N, Me₂tBuSiCl

PROCEDURE

7 mmol of base are charged to a thoroughly stirred 100 ml reactor; 30 mlof anhydrous DMF are added via a syringe. The reaction medium issubsequently brought to −10° C. and 4 equivalents of fluoroform are thenbubbled in over a period of 20 minutes.

The reaction medium is left with stirring at −10° C. for 30 minutes.

The silylating agent is subsequently added dropwise via a syringe. Thereaction medium is then allowed to return to room temperature afterwhich the amount of hemiaminal formed is assayed (¹⁹F NMR with PhOCF₃ asinternal standard).

ISOLATION OF CF₃CH(OSiMe₂tBu)NMe₂

The reaction medium is run into 30 ml of demineralized ice-water andthen extracted 3 times with 30 ml of ethyl acetate. The organic phasesare washed with demineralized ice-water until the DMF has completelydisappeared (GC monitoring) and then dried over MgSO₄ and concentratedon a rotary evaporator (θ° room, 185 mbar). The product is isolated inpure form by distillation and was characterized by ¹H, ¹³C and ¹⁹F NMR.

The use of base in a catalytic amount was then investigated inaccordance with a method of operation identical to the preceding method:

(1)/(2)/(3) RY (4) % Base (b) (a) Comments KHMDZ 4/1/1.1 33.5 base instoichiometric amount KHMDZ 4/0.1/1.1 59   base in catalytic amount (a)Fluorine NMR assay with internal standard (b) Molar ratio

EXAMPLE 14 Addition of the Anion CF₃ Obtained from CF₃SiR₃ to DMF

x (eq.) ¹⁹F NMR analysis (25° C.)⁽¹⁾ 1 CF₃H (RY = 80%), CF₃SiEt₃ (DC =100%) 0.1 CF₃H (RY = 22%) CF₃SiEt₃ (DC = 100%) and

RY = 60% ⁽¹⁾ ¹⁹F NMR assay with internal calibration.

PROCEDURE

15 ml of anhydrous DMF and 0.38 ml of CF₃SiEt₃ (2 mmol) are introducedunder argon atmosphere into a 25 ml reactor. The reaction medium iscooled to 0° C. and 0.2 ml of a 1M solution of nBu₄NF in THF (0.2 mmol)is added dropwise.

The reaction medium is left with stirring at 0° C. for 30 minutes and isthen allowed to return to room temperature.

The amount of CF₃CH(OSiEt₃)NMe₂ is determined by ¹⁹F NMR assay in thepresence of an internal standard (δ=2.9 ppm/TFA, yield=60%).

This intermediate was isolated and characterized in exactly the same wayas described in the case of CF₃CH(OSiMe₂tBu)NMe₂.

EXAMPLE 15 Return to the Tetrahedral Intermediate Anion Starting fromthe Silylated Derivative

CF₃CH(OSiMe₂tBu)NMe₂ (0.135 g) in solution in 3 ml of anhydrous DMF isintroduced under an argon atmosphere into a 5 ml reactor. The reactionmedium is cooled to −10° C. and 50 mg of tBuONa are added. The reactionmedium is analysed by low-temperature ¹⁹F NMR, and the appearance ofCF₃CH(O⁻)NMe₂ is observed (δ=1 ppm/TFA).

EXAMPLE 16 Preparation of the Tetrahedral Anion Starting from theHemiaminal

Preparation of the Hemiaminal Starting from Anhydrous Fluoral

P₂O₅ 30 g H₃PO₄ 30 g 75% w/w fluoral hydrate 6 g, or 38.8 mmol Et₂NH1.085 g, or 44.9 mmol anhydrous THF 12 ml

30 g of P₂O₅ and 30 g of H₃PO₄ are charged under an inert argonatmosphere into a 250 ml three-necked flask; this mixture is brought to95° C. (θ° of the oil bath). The assembly is connected via a Teflon pipeto a 50 ml three-necked flask fitted at the top with a dry-icecondenser.

The diethylamine and, if appropriate, the THF are charged to a 50 mlthree-necked flask; this reaction medium is brought to −40° C.

When these two temperatures have been reached, the fluoral hydrate isadded dropwise to the dehydrating mixture (dropping funnel); this isfollowed by the beginning of bubbling into the amine solution. When thisaddition is finished, the system is allowed to return to roomtemperature. The hemiaminal formed is then assayed by ¹⁹F NMR.

RY(CF₃CH(OH)NEt₂) = 76%

tBuONa −4.5 mmol  0.43 g Solution of hemiaminal −3.7 mmol  4.3 g in THFAnhydrous DMF — 25 ml Benzaldehyde −3.5 mmol  0.37 g 100% acetic acid −6mmol  0.36 g

4.5 mmol of tBuONa are charged to a stirred 100 ml reactor and 25 ml ofanhydrous DMF are added.

The reaction medium is stirred and brought to 0° C.

The hemiaminal solution is then added dropwise via a syringe through aseptum. The reaction medium is held at 0° C. for 30 minutes.

3.5 mmol of benzaldehyde are then added slowly dropwise via a syringe(slight exotherm). The reaction medium is held at 0° C. and the reactionis monitored by GC.

After 7 hours of reaction, 6.0 mmol of acetic acid are added slowly tothe reaction medium, which is then left at room temperature and assayedby GC.

RY(CF₃CH(OH)Ph)=48%

DC(PhCHO)=84%

TY(CF₃CH(OH)Ph)=57%

EXAMPLE 17 ROLE OF THE NATURE OF THE SOLVENT

A suitably stirred (400 rpm) solution of tBuOK (0.53 g, 4.7 mmol) in 30ml of anhydrous solvent (S) is admixed at −10° C. with fluoroform (3 g,42.85 mmol). The reaction medium is left with stirring at −10° C. for 30minutes before benzaldehyde is added (0.47 g, 4.4 mmol).

The solution is left with stirring at −10° C. for a further 60 minutesbefore acetic acid is added (0.5 ml).

The composition of the mixture is determined by GLC assay with internalcalibration:

Solvent RY (3) % THF 25 DMF 57 N-Formylpiperidine  5

EXAMPLE 18 ROLE OF THE NATURE OF THE BASE

T DC (3) RY (4) TY (4) RY (5) TY (5) tBUOM^((a)) θ° C. (min) (%) (%) (%)(%) (%) tBuOK −20 30 88 64 73 traces — TBuONa −20 30 83 59 71 traces —tBuOLi −20 30   32.5 13 40 traces — ^((a))CF₃H/tBuOM/PhCOH (9/1.1/1).

EXAMPLE 19 DEMONSTRATION AND ROLE OF THE TETRAHEDRAL INTERMEDIATE

{circle around (1)} Synthesis of Fluoral Hemiaminal and Derivatives

A suitably stirred solution of base in 30 ml of anhydrous DMF is admixedat −10° C. with fluoroform (3 g, 42.85 mmol). This solution is held at−10° C. for 30 minutes and then the following are added dropwise at thissame temperature:

{circle around (→)} AcOH (0.37 g, 6.2 mmol) in the case where R═H (base:KH/DMSO, 5.7 mmol);

{circle around (→)} Me₃SiCl (1.3 ml, 10.25 mmol) in the case whereR═Me₃Si (base: KHMDZ, 7 mmol); or

{circle around (→)} SO₂ (0.8 g, 12.5 mmol) in the case where R═SO₂ ⁻K⁺(base: KH/DMSO, 5.9 mmol).

The reaction medium is then held at this same temperature for 30 minutesbefore being allowed to return to room temperature.

The products formed were identified by ¹H, ¹⁹F and ¹³C NMR.

RX = AcOH, (3a), R = H RX = Me₃SiCl, (3b), R = Me₃Si RX = SO₂, (3c), R =SO₂ ⁻K⁺ RX RY (assayed) AcOH 3a, 76% Me₃SiCl 3b, 79% SO₂ 3c, 77%

{circle around (2)} Synthesis of Fluoral Hydrate

A suitably stirred solution of tBuOK (5 mmol) in an anhydrous solvent(30 ml) maintained at −15° C. is admixed with fluoroform (3 g, 42.85mmol).

After 30 minutes at this temperature, the reaction medium is acidifiedwith 2 ml of sulphuric acid.

The following table gives the results in terms of fluoral hydrate as afunction of the operating parameters:

Solvent RY (3)⁽¹⁾% DMF 60

56

52 ⁽¹⁾¹⁹F NMR assay with internal standard.

EXAMPLE 20 Synthesis of 2,2,2-trifluoroacetophenone

A suitably stirred (400 rpm) solution of KHMDZ (1.15 g, 5.75 mmol) in 30ml of anhydrous DMF is admixed at −10° C. with fluoroform (3.0 g, 43mmol). The reaction medium is left with stirring at −10° C. for 30minutes before methyl benzoate (0.51 g, 3.75 mmol) is added dropwise.

The solution is left with stirring at −10° C. for a further 1.5 hoursbefore acetic acid is added (0.6 ml). After conventional workup of thereaction medium (extraction and distillation), trifluoroacetophenone isisolated with a yield of 55%.

EXAMPLE 21 1,1,1,3,3,3-Hexafluoro-2-phenyl-2-propanol

A suitably stirred (400 rpm) solution of potassium dimesylate (5.85mmol) in 30 ml of a DMF/anhydrous DMSO mixture (2/1) is admixed at −10°C. with fluoroform (3.0 g, 43 mmol). The reaction medium is left withstirring at −10° C. for 30 minutes before trifluoroacetophenone (0.615g, 3.5 mmol) is added dropwise.

The solution is left with stirring at −10° C. for a further 1 h 10 minbefore acetic acid is added (0.6 ml).

The composition of the mixture is determined by ¹⁹F NMR assay and GLCwith internal calibration:

DC (PhCOCF₃)=35%

RY (PhCOH(CF₃)₂)=79%

TY (PhCOH(CF₃)₂)=44%

EXAMPLE 22 OTHER HALOFORMS

General Procedure

A thoroughly stirred 500 ml reactor comprising mechanical stirring (650rpm) and maintained under a nitrogen blanket is charged withapproximately 5 g of potassium tert-butoxide and then 120 ml ofanhydrous DMF. The reaction medium is then cooled to −40° C. by means ofan acetone/dry-ice bath. Approximately 5 g of benzaldehyde are thenintroduced dropwise, followed by 3 to 4 equivalents of haloform, whichis introduced by bubbling through the reaction medium if it is gaseous(CCl₂FH, CH₃CF₂H) or dropwise if it is liquid (CCl₃H). After one hour ofstirring at between −40 and −45° C., 5 ml of concentrated acetic acidare added dropwise and then the mixture is allowed to return to roomtemperature. The crude reaction medium is analysed by GLC and then byGLC/MS coupling in order to identify the product and the byproductswhich have formed.

The reaction medium is diluted in 150 ml of water and then the productsare extracted with ethyl acetate (3×170 ml). The combined organic phasesare then washed 4 to 6 times with 100 ml of water in order to remove theDMF (GLC check), then twice with 50 ml of saturated NaCl solution. Theorganic phase is then dried over anhydrous MgSO₄ for 30 to 60 minutesand thereafter is filtered on a glass frit.

If the boiling point of the compound synthesized is sufficiently high,the ethyl acetate can be evaporated on a rotary evaporator under avacuum of 20 mm Hg and at a temperature of 35° C.; otherwise, the ethylacetate is distilled at atmospheric pressure.

A fractional distillation is carried out under a vacuum of approximately15 mm Hg. In this way, the carbinol is isolated with a purity of morethan 90%

Results

DC (1) RY (4) CXYZH Boiling point^((b)) (1)^((a)) (2)^((a)) (3)^((a))(%) (%) CF₃H −80° C. 1 1 8.6 94   67 CF₃CF₂H −50° C. 1 1 4 98.5 71CCl₂FH  10° C. 1 1 3 ˜100 64 CCl₃H  60° C. 1 1 3.6 ˜100 62 ^((a))numberof equivalents ^((b))rounded, and under atmospheric pressure

EXAMPLE 23 Addition of the Anion —CF₃ (from CF₃SiMe₃) to DMF

Experiment x (eq.) ¹⁹F NMR analysis (25° C.)⁽¹⁾ 95RON57A 1 CF₃H (RY =80%), CF₃SiEt₃ (DC = 100%) 95RON57B 0.1 CF₃H (RY = 22%), CF₃SiEt₃ (DC =100%), and

RY = 60% ⁽¹⁾¹⁹F NMR assay with internal calibration.

EXAMPLE 24 TRIFLUOROMETHYLATION EXPERIMENTS USING ALKOXIDES AS THESILICOPHILIC BASE

Procedure A

In the case of the system N(SiMe₃)₃/B M⁺ (acetate and carbonates), thesilylated amine, in solution in THF, is run into a BM⁺/electrophile/fluoroform/solvent mixture.

Procedure B

In the case of the system N(SiMe₃)₃/RONa, the fluoroform is added to anN(SiMe₃)₃/RONa/electrophile/solvent mixture.

In the case of the comparative use of the alkoxides (RONa) alone as abase, the fluoroform is added to an RONa/electrophile/solvent mixture.

RESULTS Experi- Yield ment BASE (%) OH/OSiMe₃ 1 MeOna (1.5 eq.) 29 100/02 EtONa (1.5 eq.) 23 100/0 3 iPrONa (1.5 eq.) 20 100/0 4 PhONa (1.5 eq.)0 — 5 CF₃CH₂ONa (1.5 eq.) 0 — 6 (Me₃Si)₃N (1.5 eq.) + MeONa (1.5 eq.) 80100/0 7 + EtONa (1.5 eq.) 96 100/0 8 + iPrONa (1.5 eq.) 81 100/0 9 +tBuONa (1.5 eq.) 87 100/0 10 + tBuOK (0.2 eq.) 23 100/0 11 + CF₃CH₂ONa25 100/0 (1.5 eq.) 12 + PhONa (1.5 eq.) 0 — 13 + MeONa (0.2 eq.) 39 n.d.14 + MeONa (0.2 eq. 30 n.d. at −78° C.)

Procedure Using RONa as Base:

Experiments 1 to 5

Procedure B

Temperature range for the trifluoromethylation: −20° C. to +30° C.

Substrate concentration: 1 mmol in 3 ml.

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith the alcohol ROH (1.5 mmol) and sodium hydride (50%) (72 mg, 1.5mmol) in 2 ml of anhydrous DMF. After 40 minutes at 60° C. the reactionmixture is cooled to −10° C. A solution of benzophenone (182 mg, 1 mmol)in 1 ml of anhydrous DMF is introduced at −10° C. Fluoroform (400 mg,5.7 mmol) is subsequently bubbled in.

The reaction mixture is stirred at −10° C. for 1 hour. It is allowed toreturn to room temperature and is assayed by ¹⁹F NMR in the presence ofan internal standard (PhOCF₃).

Procedure Using N(SiMe₃)₃/RONa as Base System:

Experiments 6 to 12

Procedure B

Temperature range for the trifluoromethylation: −20° C. to +30° C.

Substrate concentration: 1 mmol in 3 ml.

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith the alcohol ROH (1.5 mmol) and sodium hydride (50%) (72 mg, 1.5mmol) in 1 ml of anhydrous DMF. After 40 minutes at 60° C. the reactionmixture is cooled to −10° C. A solution of tris(trimethylsilyl)amine(350 mg, 1.5 mmol) in 1 ml of anhydrous THF and a solution ofbenzophenone (182 mg, 1 mmol) in 1 ml of anhydrous DMF are introduced insuccession at −10° C. Fluoroform (400 mg, 5.7 mmol) is subsequentlybubbled in.

The reaction mixture is stirred at −10° C. for 1 hour. It is thenallowed to return to room temperature and is assayed by ¹⁹F NMR in thepresence of an internal standard (PhOCF₃).

Procedure Using N(SiMe₃)₃/B M⁺ (acetate and carbonates) as Base System:

Experiments 13 to 15

Procedure A

Temperature range for the trifluoromethylation: −20° C. to +30° C.

Substrate concentration: 1 mmol in 3 ml.

A single-necked round-bottomed 5 ml flask held under nitrogen is chargedwith the desilylating agent B—M⁺ (1.5 mmol) and benzophenone (182 mg, 1mmol) in 2 ml of anhydrous DMF. The reaction mixture is cooled to −10°C. A solution of tris(trimethylsilyl)amine (350 mg, 1.5 mmol) in 1 ml ofTHF is introduced at −10° C. Fluoroform (400 mg, 5.7 mmol) issubsequently bubbled in.

The reaction mixture is stirred at −10° C. for 1 hour. It is thenallowed to return to room temperature and is assayed by ¹⁹F NMR in thepresence of an internal standard (PhOCF₃).

What is claimed is:
 1. A reagent comprising: 1) a fluorinatedhydrocarbon compound, 2) a silicophilic base, 3) a trivalent nitrogenousderivative comprising no hydrogen and at least two silyl groups.